Despite improvements in early detection of cancer and in therapeutic interventions, overall cancer survival rates have not been markedly improved along the last decades, and metastasis is still the main cause of mortality in most solid malignancies.
It has recently become recognized that the perioperative period of primary tumor resection, namely the time period immediately before, during and following the surgical operation, enfolds several unattended risk factors for long-term cancer recurrence, and is thus characterized by high risk for the outbreak of pre-existing micrometastases and the initiation of new metastases. Most of these perioperative risks are due to various perturbations induced by the surgical removal of the primary tumor, which are believed to facilitate the progression of pre-existing micrometastases and the initiation of new metastases through several mechanisms, some of which have only recently been identified.
Numerous soluble factors are increased systemically during the perioperative period as a result of patients' neuroendocrine and paracrine responses to (i) the presence of the primary tumor, to (ii) physiological and psychological stress, and (iii) to the surgical procedure itself and its accompanying anesthesia, analgesia, blood transfusion and other intra-operative procedures. These soluble compounds include catecholamines, prostaglandins, glucocorticoids, opioids, and a variety of administered anesthetic and analgesic agents. In recent years, it has become clear that in vitro, many of these factors act directly on malignant cells, activating several molecular processes that are critical for tumor metastatic activity, including tumor cell proliferation, adhesion, locomotion, extracellular matrix invasion capacity, resistance to apoptosis and anoikis, and secretion of pro-angiogenic factors. Additionally, in vitro and human and animal in vivo studies show that many of these soluble factors lead to suppression of anti-metastatic cell mediated immunity (CMI), which is indeed a common perioperative phenomenon.
CMI, particularly cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, is suppressed even before surgery, and significantly more so following it, with the degree of suppression corresponding to the extent of surgical trauma and tissue damage. Notably, the suppression of CMI had been causally shown to mediate promotion of cancer metastasis in animal models, and clinical studies had associated it with increased susceptibility to metastatic development.
Among the various treatments aiming at reducing malignant tissue and/or preventing suppression of CMI, immunotherapy in cancer patients has regained momentum in the past decade. Specifically, type 1 T-helper (Th1) and proinflammatory cytokines (e.g. IL-2, IL-12, IFN-γ) are known to significantly enhance CMI, which plays a crucial role in the in vivo eradication of malignant cells. Immune-stimulatory approaches (ISAs) commonly utilize established biological response modifiers (BRMs), which include natural or synthetic compounds containing pathogen-associated molecular patterns (e.g. LPS, CpG), or the pro-inflammatory/Th1 cytokines that these compounds induce.
However, while animal studies employing anti-tumor ISAs showed promising results, clinical studies in cancer patients were, by-and-large, less successful. Several difficulties in simulating the development of human cancer in animal models were suggested to underlie this discrepancy, most focusing on differences in the biology of the implanted cancerous tissue and host physiology, including immune susceptibility and compatibility to implanted tissue. Stress responses, known to induce an immunossupressing effect, which result from psychological and physiological conditions that characterize cancer patients and absent in animal models, were also suggested to underlie this discrepancy.
Neeman et al. (2012) Clin Cancer Res., 18(18): 4895-902 describe an approach to reducing postsurgical cancer recurrence, by perioperative targeting of catecholamines and prostaglandins using simultaneous beta-adrenergic blockade and COX-2 inhibition.
Avraham et al. (2010) Brain Behav Immun., 24(6):952-8 describe an integration of immunostimulatory therapy with endocrine-blocker pharmacological interventions that prevent postoperative immunosuppression, to reduce post-operative tumor progression.
Despite the acknowledged importance of the perioperative period, and the promising results evident in animal studies employing ISAs, immune-stimulatory therapy has rarely been utilized in patients during the perioperative period, presumably due to the expected pyrogenic and adverse effects of ISAs that cannot be distinguished from signs of life-threatening infections in the context of surgery. The relatively few clinical trials that had attempted this approach utilized a single Th1 (e.g., IL-2, IL-12) or a proinflammatory (e.g., IFN-α) cytokine, and have indeed reported severe adverse reactions to these therapies, including leukopenia, deterioration of performance status, fever, vomiting, and mental depression. Recently FDA-approved synthetic agents, which are based on pathogen-associated molecular patterns (PAMPs), have been shown to cause markedly less adverse reactions while inducing an effective, self-controlled, endogenous, multi-cytokine response. Such ISAs include the TLR-4 agonists, termed glucopyranosyl lipid adjuvants (GLAs as disclosed in U.S. Pat. No. 8,273,361 and WO 2010/141861), which activate T, B, and Dendritic cells.
U.S. Pat. No. 8,273,361 discloses compositions and methods, including vaccines and pharmaceutical compositions for inducing or enhancing an immune response, based on the discovery of useful immunological adjuvant properties of a synthetic, glucopyranosyl lipid adjuvant (GLA) that is provided in a substantially homogeneous chemical form. Also provided are vaccines and pharmaceutical compositions that include GLA and one or more antigens, a Toll-like receptor (TLR) agonist, a co-adjuvant and a carrier such as a pharmaceutical carrier.
WO 2010/141861 discloses compounds, particularly, glucopyranosyl lipid adjuvant (GLA) compounds with an alternate chemical structures and properties. Pharmaceutical compositions, vaccine compositions, and related methods for inducing or enhancing immune responses, are also disclosed.
There still remains a need for more effective treatments against the development of metastases.
All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.